The etiology of preeclampsia remains unknown, but is hypothesized to result from abnormal placentation. One of the most common complications of pregnancy, with US incidence rates between 2 per cent and 7 per cent in healthy primiparous women, abnormal placentation carries a substantial risk for maternal and fetal morbidity and mortality. Although maternal smoking increases the risk of several major pregnancy complications, it paradoxically decreases the risk of preeclampsia by an estimated 30 per cent, which may provide unexploited clues into the etiology of this disorder. We propose to utilize the Norwegian Mother and Child Cohort Study, a large population-based birth cohort with over 86,000 pregnancies currently enrolled, to address the following specific aims in relation to risk of preeclampsia: 1) Examine maternal and fetal genetic variation in the apoptosis, smoking detoxification, angiogenesis and inflammation pathways; 2) Examine the joint effects of active and passive smoking exposure and the gene variants described above; and 3) Examine the joint effects of multiple at-risk alleles. We will select 1500 validated, singleton preeclampsia cases from whom both maternal and cord blood was collected and match them to randomly selected controls with available biospecimens. Maternal and fetal DNA will be extracted and genotyped using the Illumina Goldengate 1536 custom chip, which will allow us to measure gene-wide variation in approximately 93 genes. Additionally, ancestry informative markers will be included to control for potential population stratification. We will over-sample maternal smoking among cases to achieve a smoking prevalence approximately equal to controls of 11 per cent, which will provide us excellent power to detect gene-environment interactions, even for relatively rare alleles. Given that large-scale genetic studies of preeclampsia have not previously been reported; that the candidate-gene pathways we propose are both novel and biologically plausible; and that fetal genetic variation has not previously been assessed in relation to preeclampsia despite the fact that the placenta is of fetal genetic origin, this project will provide important new information relevant to the etiology of preeclampsia. PUBLIC HEALTH RELEVANCE: This study promises to generate a markedly enhanced understanding of the genetic epidemiology of preeclampsia given our large study size and excellent power to detect main and interaction effects; the ability to consider both maternal and fetal genes; the breadth and depth of genetic assessment; and the availability of maternally reported smoking status during pregnancy, a well-established cause of reduced risk for preeclampsia. This information will provide a foundation for studying other adverse pregnancy outcomes with shared biological mechanisms.